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Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

ObjectivePrimary Sjögren's syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is a disease of the salivary gland, we investigated anti-SSA/Ro52 in saliva.MethodsUsing a novel electrochemical detection platform, Electric Field-Induced Release and Measurement, we measured IgG/M/A, IgG, IgA, IgA isotypes (IgA1 and IgA2) and IgA1 subclasses (polymeric and monomeric IgA1) to anti-SSA/Ro52 in saliva supernatant of 34 pSS, 35 dry eyes and dry mouth (patients with Sicca) and 41 health controls.ResultsSaliva IgG/M/A, IgG, IgA, IgA isotypes and IgA1 subclasses to anti-SSA/Ro52 differed significantly between pSS, non-pSS Sicca and healthy subjects. Elevated monomeric IgA1 was observed in patients with non-pSS Sicca while elevated polymeric IgA1 (pIgA1) was observed in patients with pSS. Salivary polymeric but not monomeric IgA1 (mIgA1) isoform correlated with focus score (r2=0.467, p=0.001) CONCLUSIONS: Salivary anti-Ro52 polymeric IgA1 isoform is associated with glandular inflammation in pSS, while salivary monomeric IgA1 is associated with Sicca. Whether IgA1 isotope switching plays a role in the progression of the Sicca to pSS warrants further investigation.

Introduction: Despite progress in our understanding of disease pathogenesis for systemic autoimmune rheumatic diseases (SARD), these diseases are still associated with high morbidity, disability, and mortality. Much of the strongest evidence to date implicating environmental factors in the development of autoimmunity has been based on well-established, large, longitudinal prospective cohort studies. Methods: Herein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research. Results: The risk attributable to any particular environmental factor ranges from 10-200%, but exposures are likely synergistic in altering the immune system in a complex interplay of epigenetics, hormonal factors, and the microbiome leading to systemic inflammation and eventual organ damage. To reduce or forestall the progression of autoimmunity, a better understanding of disease pathogenesis is still needed. Conclusion: Owing to the complexity and multifactorial nature of autoimmune disease, machine learning, a type of artificial intelligence, is increasingly utilized as an approach to analyzing large datasets. Future studies that identify patients who are at high risk of developing autoimmune diseases for prevention trials are needed. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Methods: Pre‐diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen‐2 (IA‐2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t‐tests. Results: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody‐positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA‐positivity was higher in insulin‐treated relatives than in non‐insulin‐treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA‐positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody‐positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). Conclusion: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis. [ABSTRACT FROM AUTHOR]

Environmental disasters are extreme environmental processes such as earthquakes, volcanic eruptions, landslides, tsunamis, floods, cyclones, storms, wildfires and droughts that are the consequences of the climate crisis due to human intervention in the environment. Their effects on human health have alarmed the global scientific community. Among them, autoimmune diseases, a heterogeneous group of disorders, have increased dramatically in many parts of the world, likely as a result of changes in our exposure to environmental factors. However, only a limited number of studies have attempted to discover and analyze the complex association between environmental disasters and autoimmune diseases. This narrative review has therefore tried to fill this gap. First of all, the activation pathways of autoimmunity after environmental disasters have been analyzed. It has also been shown that wildfires, earthquakes, desert dust storms and volcanic eruptions may damage human health and induce autoimmune responses to inhaled PM2.5, mainly through oxidative stress pathways, increased pro-inflammatory cytokines and epithelial barrier damage. In addition, it has been shown that heat stress, in addition to increasing pro-inflammatory cytokines, may also disrupt the intestinal barrier, thereby increasing its permeability to toxins and pathogens or inducing epigenetic changes. In addition, toxic volcanic elements may accelerate the progressive destruction of myelin, which may potentially trigger multiple sclerosis. The complex and diverse mechanisms by which vector-borne, water-, food-, and rodent-borne diseases that often follow environmental diseases may also trigger autoimmune responses have also been described. In addition, the association between post-disaster stress and the onset or worsening of autoimmune disease has been demonstrated. Given all of the above, the rapid restoration of post-disaster health services to mitigate the flare-up of autoimmune conditions is critical. [ABSTRACT FROM AUTHOR]

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.

The Ro60/SSA2 autoantigen is an RNA-binding protein and a core component of nucleocytoplasmic ribonucleoprotein (RNP) complexes. Ro60 is essential in RNA metabolism, cell stress response pathways, and cellular homeostasis. It stabilises and mediates the quality control and cellular distribution of small RNAs, including YRNAs (for the 'y' in 'cytoplasmic'), retroelement transcripts, and misfolded RNAs. Ro60 transcriptional dysregulation or loss of function can result in the generation and release of RNA fragments from YRNAs and other small RNAs. Small RNA fragments can instigate an inflammatory cascade through endosomal toll-like receptors (TLRs) and cytoplasmic RNA sensors, which typically sense pathogen-associated molecular patterns, and mount the first line of defence against invading pathogens. However, the recognition of host-originating RNA moieties from Ro60 RNP complexes can activate inflammatory response pathways and compromise self-tolerance. Autoreactive B cells may produce antibodies targeting extracellular Ro60 RNP complexes. Ro60 autoantibodies serve as diagnostic markers for various autoimmune diseases, including Sjögren's disease (SjD) and systemic lupus erythematosus (SLE), and they may also act as predictive markers for anti-drug antibody responses among rheumatic patients. Understanding Ro60's structure, function, and role in self-tolerance can enhance our understanding of the underlying molecular mechanisms of autoimmune conditions. [ABSTRACT FROM AUTHOR]

While it is known that immunoglobulin replacement therapy (IgRT) used in the treatment of primary immunodeficiency disorders (PIDs) can lead to the passive transfer of autoantibodies, there is no data indicating that these antibodies can cause clinical symptoms in patients. This study aimed to investigate the presence of autoantibodies and their clinical correlation in patients diagnosed with PIDs receiving IgRT. Paediatric patients who were diagnosed with PIDs, and administered IgRT at our immunology clinic between 1 January 2012 and 31 December 2021, were included in the study. The medical records of these patients were retrospectively analysed, and autoantibodies were screened. Autoantibody screening was conducted at least once in 48 cases. Among these cases, 29 cases (60.4%) demonstrated positivity for at least one of the autoantibodies screened in the study. Among these cases, 23 tested positive for anti‐TPO, 9 for anti‐TG and 2 for both anti‐TPO and anti‐TG. Only two of these patients were confirmed to have Hashimoto's thyroiditis. In 30 cases, autoantibodies related to Celiac disease (CD) were screened, with at least one being positive in five different cases; CD was not confirmed. The results of our study suggest that passive transfer of autoantibodies to patients with IgRT does not cause any significant clinical findings. In addition, in cases of PID, autoantibodies detected in the blood passed to patients with IgRT can lead to misdiagnosis. Screening for autoantibodies in patients with PID undergoing IgRT may not yield accurate results in terms of detecting autoimmune diseases. [ABSTRACT FROM AUTHOR]

The given text is a list of references to various scientific articles related to immunology and autoimmune diseases. The articles cover topics such as the influence of HLA class II molecules on inflammatory diseases, the role of DNases in health and disease, polymorphisms associated with rheumatoid arthritis, and the overlap in neutrophil transcriptome between lupus and COVID-19. Other articles discuss the role of alternative splicing in cancer and autoimmune diseases, the expression of retroviruses in rheumatoid arthritis and lupus, and the presence of autoantibodies in autoimmune diseases. These articles provide valuable insights into the mechanisms and potential therapeutic targets for these diseases. [Extracted from the article]

Autoimmune diseases are characterized by the recognition of self-antigens autoantigens) by immune system cells. Loss of immunological tolerance may lead to the generation of autoantibodies and, consequently, tissue damage. It has already been proven that highly immunogenic bacterial and autologous extracellular heat shock proteins (eHsps) interact with immune cells of the innate and adaptive arms of the immune system. The latter interactions may stimulate a humoral (auto)immune response and lead to the generation of anti- Hsps (auto)antibodies. Although circulating levels of anti-Hsps autoantibodies are often elevated in patients suffering from multiple inflammatory and autoimmune diseases, their role in the development of pathological conditions is not fully established. This mini-review presents the dual role of anti-Hsps autoantibodies - protective or pathogenic - in the context of the development of selected autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Neuronal nicotinic acetylcholine receptors (nAChRs) are abundant in the central nervous system (CNS), playing critical roles in brain function. Antigenicity of nAChRs has been well demonstrated with antibodies to ganglionic AChR subtypes (i.e., subunit a3 of a3b4-nAChR) and muscle AChR autoantibodies, thus making nAChRs candidate autoantigens in autoimmune CNS disorders. Antibodies to several membrane receptors, like NMDAR, have been identified in autoimmune encephalitis syndromes (AES), but many AES patients have yet to be unidentified for autoantibodies. This study aimed to develop of a cell-based assay (CBA) that selectively detects potentially pathogenic antibodies to subunits of the major nAChR subtypes (a4b2- and a7-nAChRs) and its use for the identification of such antibodies in "orphan" AES cases. Methods: The study involved screening of sera derived from 1752 patients from Greece, Turkey and Italy, who requested testing for AES-associated antibodies, and from 1203 "control" patients with other neuropsychiatric diseases, from the same countries or from Germany. A sensitive live-CBA with a4b2-or a7-nAChR-transfected cells was developed to detect antibodies against extracellular domains of nAChR major subunits. Flow cytometry (FACS) was performed to confirm the CBA findings and indirect immunohistochemistry (IHC) to investigate serum autoantibodies' binding to rat brain tissue. Results: Three patients were found to be positive for serum antibodies against nAChR a4 subunit by CBA and the presence of the specific antibodies was quantitatively confirmed by FACS. We detected specific binding of patientderived serum anti-nAChR a4 subunit antibodies to rat cerebellum and hippocampus tissue. No serum antibodies bound to the a7-nAChR-transfected or control-transfected cells, and no control serum antibodies bound to the transfected cells. All patients positive for serum anti-nAChRs a4 subunit antibodies were negative for other AES-associated antibodies. All three of the anti-nAChR a4 subunit serum antibody-positive patients fall into the AES spectrum, with one having Rasmussen encephalitis, another autoimmune meningoencephalomyelitis and another being diagnosed with possible autoimmune encephalitis. Conclusion: This study lends credence to the hypothesis that the major nAChR subunits are autoimmune targets in some cases of AES and establishes a sensitive live-CBA for the identification of such patients. [ABSTRACT FROM AUTHOR]

To carry out an in-depth analysis of the scientific research on autoimmunity, we performed the first bibliometric analysis focusing on publications in journals dedicated to autoimmunity (JDTA) indexed by science citation index during the period 2004–2023. Using bibliometric analysis, we quantitatively and qualitatively analyzed the country, institution, author, reference and keywords information of publications in JDTA, so as to understand the quantity, publication pattern and publication characteristics of these publications. The co-occurrence networks, clustering map and timeline map were created by CiteSpace and VOSviewer software to visualize the results. The CiteSpace was also used to analyze the strongest citation burst of keywords, which could describe the frequency, intensity and time period of high-frequency keywords, and indicate the research hotspots in the field. A total of 5 710 publications were analyzed, and their annual distribution number was basically stable from 2004 to 2023, fluctuating around 300. The United States and Italy led the way in terms of the number of publications, followed by France and China. For international cooperation, the developed countries represented by the United States cooperate more closely, but the cooperation was localized, reflecting that there was no unified model of autoimmunity among countries. UDICE-French Research Universities had the greatest number of publications. Subsequently, the number of publications decreased slowly with the ranking, and the gradient was not large. Eric Gershwin and Yehuda Shoenfeld stood out among the authors. They had an excellent academic reputation and great influence in the field of autoimmunity. The results of keyword analysis showed that JDTA publications mainly studied a variety of autoimmune diseases, especially SLE and RA. At the same time, JDTA publications also paid special attention to the research of cell function, autoantibody expression, animal experiments, disease activity, pathogenesis and treatment. This study is the first to analyze the publications in JDTA from multiple indicators by bibliometrics, thus providing new insights into the research hotspots and development trends in the field of autoimmunity. [ABSTRACT FROM AUTHOR]

Background and purpose: Paraneoplastic neurological autoimmunity is well described with small‐cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). Methods: Adult patients with histopathologically confirmed non‐pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). Results: Thirty‐four patients were identified (median age 68 years, range 31–87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non‐ICI‐treated patients. The most frequent neurological phenotypes (non‐ICI‐treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q‐type voltage‐gated calcium channel [seven], muscle‐type acetylcholine receptor [three], anti‐neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non‐ICI‐treated) and neural autoantibody positivity was associated with poor neurological outcome. Discussion: Neurological autoimmunity associated with non‐pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment. [ABSTRACT FROM AUTHOR]

IntroductionDespite progress in our understanding of disease pathogenesis for systemic autoimmune rheumatic diseases (SARD), these diseases are still associated with high morbidity, disability, and mortality. Much of the strongest evidence to date implicating environmental factors in the development of autoimmunity has been based on well-established, large, longitudinal prospective cohort studies.MethodsHerein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research.ResultsThe risk attributable to any particular environmental factor ranges from 10-200%, but exposures are likely synergistic in altering the immune system in a complex interplay of epigenetics, hormonal factors, and the microbiome leading to systemic inflammation and eventual organ damage. To reduce or forestall the progression of autoimmunity, a better understanding of disease pathogenesis is still needed.ConclusionOwing to the complexity and multifactorial nature of autoimmune disease, machine learning, a type of artificial intelligence, is increasingly utilized as an approach to analyzing large datasets. Future studies that identify patients who are at high risk of developing autoimmune diseases for prevention trials are needed.

Background: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. Study Design and Methods: Using binding‐capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor‐derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. Results: Anti‐thyroglobulin (Tg), anti‐thyroidperoxidase (TPO), and anti‐Sjögren's‐syndrome‐related antigen A (SS‐A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. Discussion: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false‐positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy. [ABSTRACT FROM AUTHOR]

Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity. [ABSTRACT FROM AUTHOR]

Primary Sjögren's disease (pSD) (also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell–intrinsic TLR7 activation is integral to the pathogenesis of systemic lupus erythematosus, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABCs exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared with those derived from control animals. Sort-purified marginal zone B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for antinuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated antinuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine marginal zone B cells and ABCs. These data indicate that pSD B cells are hyperresponsive to TLR7 agonism and that TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients. [ABSTRACT FROM AUTHOR]

Immunoglobulins are an essential part of the humoral immune response. IgG4 antibodies are the least prevalent subclass and have unique structural and functional properties. In this review, we discuss IgG4 class switch and B cell production. We review the importance of IgG4 antibodies in the context of allergic responses, helminth infections and malignancy. We discuss their anti-inflammatory and tolerogenic effects in allergen-specific immunotherapy, and ability to evade the immune system in parasitic infection and tumour cells. We then focus on the role of IgG4 autoantibodies and autoantigens in IgG4-autoimmune diseases and IgG4-related disease, highlighting important parallels and differences between them. In IgG4-autoimmune diseases, pathogenesis is based on a direct role of IgG4 antibodies binding to selfantigens and disturbing homeostasis. In IgG4-related disease, where affected organs are infiltrated with IgG4-expressing plasma cells, IgG4 antibodies may also directly target a number of self-antigens or be overexpressed as an epiphenomenon of the disease. These antigen-driven processes require critical T and B cell interaction. Lastly, we explore the current gaps in our knowledge and how these may be addressed. [ABSTRACT FROM AUTHOR]

Objective: Autoimmune diseases commonly feature the presence of specific humoral autoantibodies. However, the prevalence of a large panel of systemic autoantibodies has never been assessed in the general population. We, therefore, described the prevalence of about 50 humoral systemic autoantibodies in a sample of the general Bavarian adult population. Methods: Non-fasting venous serum samples from 331 participants were analyzed for 7 autoantibody screening tests (nuclear, cytoplasmic, and mitotic ANA, ANCA, cANCA and pANCA, anti-ENA autoantibodies) and 44 different monospecific humoral non-organ specific/systemic autoantibodies using indirect immunofluorescence tests, ELISAs, and line blots. In order to assess associations between sex, age, BMI, education level, smoking status and the presence of systemic autoantibodies, logistic regression analyses were conducted. Results: At least one screening test was positive in 29.9% of the participants, and 42.3% of the participants were seropositive for at least one monospecific autoantibody. The most frequently found monospecific autoantibodies were rheumatoid factor (35.6%), ß2-glycoprotein 1 IgM (4.8%), and cardiolipin IgG (1.8%). Only few associations between sex, age, BMI, education, smoking status and autoantibody frequencies were observed. Conclusion: Systemic autoantibodies are common in the general Bavarian population, and largely independent of sex, age, BMI, education, or smoking status. The study results may give orientation to clinicians about the occurrence of autoantibodies in the population, not (yet) associated with clinical symptoms. [ABSTRACT FROM AUTHOR]

COVID‐19 is a severe infectious disease caused by a SARS‐CoV‐2 infection. It has caused a global pandemic and can lead to acute respiratory distress syndrome (ARDS). Beyond the respiratory system, the disease manifests in multiple organs, producing a spectrum of clinical symptoms. A pivotal factor in the disease's progression is autoimmunity, which intensifies its severity and contributes to multi‐organ injuries. The intricate interaction between the virus' spike protein and human proteins may engender the generation of autoreactive antibodies through molecular mimicry. This can further convolute the immune response, with the potential to escalate into overt autoimmunity. There is also emerging evidence to suggest that COVID‐19 vaccinations might elicit analogous autoimmune responses. Advanced technologies have pinpointed self‐reactive antibodies that target diverse organs or immune‐modulatory proteins. The interplay between autoantibody levels and multi‐organ manifestations underscores the importance of regular monitoring of serum antibodies and proinflammatory markers. A combination of immunosuppressive treatments and antiviral therapy is crucial for managing COVID‐19‐associated autoimmune diseases. The review will focus on the generation of autoantibodies in the context of COVID‐19 and their impact on organ health. [ABSTRACT FROM AUTHOR]

The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of antitumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the antitumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship. [ABSTRACT FROM AUTHOR]

ObjectiveThe ability to regulate B cell development has long been recognized to have therapeutic potential in a variety of autoimmune diseases. However, despite the presence of a classic autoantibody in primary biliary cholangitis (PBC), B cell depleting therapy and indeed therapy with other biologic agents has been disappointing. Unsuccessful treatment using Rituximab is associated with elevation of B-cell activating factor (BAFF) level. Indeed, therapies for PBC remain directed at modulating bile salt biology, rather than targeting effector pathways. With these data in mind, we proposed that targeting two major stages of B cell development, namely long-lived memory B cells and short-lived peripheral autoreactive plasma cells would have therapeutic potential.MethodsTo address this thesis, we administrated anti-BAFF and anti-CD20 monoclonal antibody to ARE-Del mice, a well-characterized murine model of human PBC. We evaluated and compared the therapeutic efficacy of the two agents individually and the combination of anti-BAFF and anti-CD20 in female mice with well-established disease.ResultsOur data demonstrate that there was an increased level of B cell depletion that resulted in a significantly more effective clinical and serologic response using the combination of agents as compared with the use of the individual agents. The combination of anti-BAFF and anti-CD20 treatment was more effective in reducing serum levels of antimitochondrial antibody (AMA), total IgM and IgG compared to mice treated with the 2 individual agents. Combination treatment efficiently depleted B cells in the peripheral blood, peritoneal cavity and spleen. Importantly, we identified a unique IgM+ FCRL5+ B cell subset which was sensitive to dual B-cell targeting therapy and depletion of this unique population was associated with reduced portal infiltration and bile duct damage. Taken together, our data indicate that dual B cell targeting therapy with anti-BAFF and anti-CD20 not only led to the efficient depletion of B cells both in the peripheral blood and tissues, but also led to significant clinical improvement. These findings highlight the potential application of combination of anti-BAFF and anti-CD20 in treating patients with PBC. However, additional studies in other animal models of PBC should be undertaken before considering human trials in those PBC patients who have incomplete responses to conventional therapy.

Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

The interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/- mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis.

Objective: Several immunological factors are emphasized in the etiology of autoimmune thyroid diseases and obsessivecompulsive disorder. Obsessive-compulsive symptoms (OCS) are commonly seen in patients with autoimmune thyroid diseases. This study aims to evaluate the relationship between OCS and antithyroid antibodies. Methods: The study included 145 patients with Hashimoto thyroiditis or Graves’ disease and 42 healthy controls. Thyroid function tests and serum thyroid autobody levels (anti-thyroglobulin [TG], anti-thyroid peroxidase [TPO], and anti-thyroid stimulating hormone [TSH]) of the patients were measured. The socio-demographic data and OCS of the participants were evaluated with Dimensional OCS (DOCS). Results: DOCS scores were higher in patients than in the control group. There was not found a significant relationship between free T3, free T4, and TSH levels and DOCS scores. Anti-TG positivity in females was associated with lower DOCS scores. Anti-TPO positivity in males had a positive correlation with DOCS scores. There was no correlation between sex and the presence of anti-TSH in terms of OCS severity. Univariate analysis found the highest OCS scores in anti-TPO positive, anti-TG, and anti-TSH negative patients. The group with the lowest OCS scores was found to be anti-TG positive, anti-TPO, and anti-TSH negative patients. Conclusion: OCS severity could be affected by different thyroid autoantibody profiles in patients with autoimmune thyroid diseases. While anti-TG serves a protective role against OCS in females, the presence of anti-TPO may worsen the OCS in men. Additionally, the co-existence of different antithyroid antibodies may affect the severity of OCS differently according to sex. [ABSTRACT FROM AUTHOR]

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs). Methods: Serum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays. Results: Of the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak. Discussion: Our findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE. [ABSTRACT FROM AUTHOR]

Autoimmunity and its associated diseases have been the primary area of focus in research in the past decade; however, several mechanisms are still left unclear. Autoimmune diseases are idiopathic and currently, there are hardly any genetic tools available to predict who is at risk of developing them. With the advancement of artificial intelligence, it could be possible to predict the potential emergence of autoimmune disorders. This review article discusses the disease classification and relevant causes, including environmental, biological, and genetic factors. Additionally, it explores certain mechanisms where the T-regulatory cells fail and lead to disease development. The article delves into the etiology to illustrate how autoimmune diseases could develop in a person as well as therapeutic approaches are also discussed. With the development of multiplex technologies, it is easier to detect autoantibodies in blood while cytokines and chemokines can give a breakthrough in diagnosis and novel therapeutics for these diseases. [ABSTRACT FROM AUTHOR]

Gigantomastia is a rare entity characterized by diffuse and excessive breast enlargement. It mainly occurs during puberty and pregnancy as a consequence of hormonal fluctuations. We report an unusual case of gigantomastia in a 29‐year‐old woman with a history of personal and familiar autoimmune phenomena. She had autoimmune thyroiditis and several positive autoantibodies, and developed 3 crises of the disease, 1 related to pregnancy (possibly hormone‐mediated), and 2 unrelated to pregnancy in which an autoimmune role is raised based in clinical, histological and laboratory findings. Immunological aspects that may be involved in this presentation of the disease are discussed. [ABSTRACT FROM AUTHOR]

Autoimmune encephalitides are seldom diseases. How rare they actually are, however, is not known. The low incidence combined with the problematic identification may dampen efforts of neurologists, to identify patients with unclear symptoms as suffering from autoimmune encephalitis. Here, we aim to obtain a better estimate, how many patients with autoimmune disorders should be expected among 100 inpatients in a conventional neurological department. From a total number of 2603 non-stroke patients attended in a 2-year period (2018–2019) 460 CSFs were obtained. From this collection 187 samples (40.7%, > 500 sections) could be analyzed with our immunocytochemical technique. Autoreactive antibodies were detected in 102 (55%) of these 187 CSF samples. Certainly, the presence of autoreactive antibodies does not necessarily indicate that the patient suffers from an autoimmune disease. Our data indicate that from roughly 2000 patients during 1 year about 125 patients with autoreactive CSF antibodies should be expected in a conventional neurological department. This represents the about 35-fold value of what is generally expected at present. Being aware of this high incidence may intensify the efforts of neurologist to identify patients with any type of autoimmune encephalitis. This will be beneficial for patients, because they often profit from immunomodulatory therapy. Interestingly, some CFSs from our patients react with the CA2 subdivision of the hippocampus. While long neglected, recent research places this area into an important position to influence hippocampal network physiology. Autoreactive antibodies in the CSF may disturb the function of CA2 neurons, thereby explaining some neuropsychiatric symptoms in patients with autoimmune encephalitides. [ABSTRACT FROM AUTHOR]

The worldwide prevalence of autoimmune diseases that have limited treatment options and preventive strategies is rapidly rising. There is growing evidence that the microbiota and the integrity of the intestinal barrier play a role in autoimmune diseases. The potential to evaluate intestinal barrier integrity for susceptible individuals and to determine whether restoring intestinal junction integrity impacts autoimmune diseases is an important area of research that requires further attention. In the intestinal permeability model of autoimmune diseases, the breakdown of the intestinal tight junction proteins (zonulin/occludin) allows bacteria, toxins, undigested dietary proteins, and other antigens to pass into the lumen, thereby increasing the number of inflammatory reactions and the activation of immune cells throughout the body. In this study, we investigate the relationship between zonulin/occludin antibodies, which are used to determine intestinal permeability, with autoantibodies used to diagnose autoimmunity. Our investigation may identify significant levels of circulating autoantibodies in human subjects with intestinal permeability compared to those without intestinal permeability. Furthermore, we identified that significant positive linear correlations between serum occludin/zonulin antibodies and circulating autoantibodies could be used to determine autoimmune diseases. [ABSTRACT FROM AUTHOR]

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Introduction: The association of human immunodeficiency virus (HIV) infection with the development of autoimmune disorders or systemic diseases is intriguing. Here, we describe a case of HIVpositive individual, who developed a bullous pemphigoid with several autoimmune disorders. Case description: A 58 year-old man was admitted to infectious diseases department in June, 2020 due to fever and blistering skin lesions. After several investigations, diagnosis of HIV infection and nodal tuberculosis as opportunistic infection, associated with a bullous pemphigoid was made. Topical corticosteroids and anti-tuberculosis therapy began in June, 2020. Antiretroviral therapy started in August, 2020, with a good virological response. Four months later, in December 2020, the patient developed polyarthralgia and bilateral episcleritis. Testing for anti-nuclear antibodies and rheumatoid factors were positive. Autoimmune diseases were suspected, and the patient was treated with oral corticosteroids for two months with favorable outcome. However, in July, 2021, after the end of corticotherapy, clinical signs reappeared and the patient died of an acute kidney failure. Conclusions: Pathophysiology of autoimmune diseases in HIV population remains uncertain. There are several issues that need further studies regarding therapy, especially when systemic corticosteroids and immunosuppressive drugs are under consideration. [ABSTRACT FROM AUTHOR]

Comprehensive autoantibody evaluation is essential for the management of autoimmune disorders. However, conventional methods suffer from poor sensitivity, low throughput, or limited availability. Here, using a proteome-wide human cDNA library, we developed a novel multiplex protein assay (autoantibody array assay; A-Cube) covering 65 antigens of 43 autoantibodies that are associated with systemic sclerosis (SSc) and polymyositis/dermatomyositis (PM/DM). The performance of A-Cube was validated against immunoprecipitation and established enzyme-linked immunosorbent assay. Further, through an evaluation of serum samples from 357 SSc and 172 PM/DM patients, A-Cube meticulously illustrated a diverse autoantibody landscape in these diseases. The wide coverage and high sensitivity of A-Cube also allowed the overlap and correlation analysis between multiple autoantibodies. Lastly, reviewing the cases with distinct autoantibody profiles by A-Cube underscored the importance of thorough autoantibody detection. Together, these data highlighted the utility of A-Cube as well as the clinical relevance of autoantibody profiles in SSc and PM/DM. [ABSTRACT FROM AUTHOR]

Group A streptococcus (GAS) is a global pathogen associated with significant morbidity and mortality for which there is currently no licensed vaccine. Vaccine development has been slow, mostly due to safety concerns regarding streptococcal antigens associated with autoimmunity and related complications. For a GAS vaccine to be safe, it must be ensured that the antigens used in the vaccine do not elicit an antibody response that can cross-react with host tissues. In this study, we evaluated the safety of our GAS vaccine candidate called VaxiStrep in New Zealand White rabbits. VaxiStrep is a recombinant fusion protein comprised of streptococcal pyrogenic exotoxin A (SpeA) and exotoxin B (SpeB), also known as erythrogenic toxins, adsorbed to an aluminum adjuvant. The vaccine elicited a robust immune response against the two toxins in the rabbits without any adverse events or toxicity. No signs of autoimmune pathology were detected in the rabbits' brains, hearts, and kidneys via immunohistochemistry, and serum antibodies did not cross-react with cardiac or neuronal tissue proteins associated with rheumatic heart disease or Sydenham chorea (SC). This study further confirms that VaxiStrep does not elicit autoantibodies and is safe to be tested in a first-in-human trial. [ABSTRACT FROM AUTHOR]

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. We find raised levels of anti-DSG2 autoantibodies in sera from individuals following severe COVID-19. Staining of post-mortem cardiac tissue from individuals that died from COVID-19 with an anti-DSG2 antibody revealed disruption of the intercalated disc between cardiomyocytes that was consistent with separation of the DSG2 protein homodimer. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. [ABSTRACT FROM AUTHOR]

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta‐cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen‐2 (IA‐2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high‐risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first‐appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first‐appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3–4 years of age. GADA first appeared by 2–3 years of age to reach a plateau by about 4 years. Prior to the first‐appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D. [ABSTRACT FROM AUTHOR]

Type I IFNs are critical for host responses to viral infection and are also implicated in the pathogenesis of multiple autoimmune diseases. Multiple subtypes exist within the type I IFN family, in particular 13 distinct IFN‐α genes, which signal through the same heterodimer receptor that is ubiquitously expressed by mammalian cells. Both evolutionary genetic studies and functional antiviral assays strongly suggest differential functions and activity between the 13 IFN‐α subtypes, yet we still lack a clear understanding of these different roles. This review summarizes the evidence from studies describing differential functions of IFN‐α subtypes and highlights potential reasons for discrepancies between the reports. We examine both acute and chronic viral infection, as well as autoimmunity, and integrate a more recent awareness of the importance of anti‐IFN‐α autoantibodies in shaping the type I IFN responses in these different conditions. [ABSTRACT FROM AUTHOR]

IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects. [ABSTRACT FROM AUTHOR]

The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune‐mediated neuropathies. Our understanding of the specialized nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin‐140/186, neurofascin‐155, contactin‐1, contactin‐associated protein 1, contactin‐associated protein 2, gangliosides, LGI4, or myelin‐associated glycoprotein), macrophage‐induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue, and autoimmune disease with the highest case-specific mortality and complications among rheumatic diseases. It is characterized by complex and variable features such as autoimmunity and inflammation, vasculopathy, and fibrosis, which pose challenges in understanding the pathogenesis of the disease. Among the large variety of autoantibodies (Abs) present in the sera of patients suffering from SSc, functionally active Abs against G protein-coupled receptors (GPCRs), the most abundant integral membrane proteins, have drawn much attention over the last decades. These Abs play an essential role in regulating the immune system, and their functions are dysregulated in diverse pathological conditions. Emerging evidence indicates that functional Abs targeting GPCRs, such as angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), are altered in SSc. These Abs are part of a networkwith severalGPCR Abs, such as those directed to the chemokine receptors or coagulative thrombin receptors. In this review, we summarize the effects of Abs against GPCRs in SSc pathologies. Extending the knowledge on pathophysiological roles of Abs against GPCRs could provide insights into a better understanding of GPCR contribution to SSc pathogenesis and therefore help in developing potential therapeutic strategies that intervene with pathological functions of these receptors. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that SARS‐CoV‐2 can potentially trigger autoimmune processes, which can be responsible for the long‐term consequences of COVID‐19. Therefore, this paper aims to review the autoantibodies reported in COVID‐19 convalescents. Six main groups were distinguished: (i) autoantibodies against components of the immune system, (ii) autoantibodies against components of the cardiovascular system, (iii) thyroid autoantibodies, (iv) autoantibodies specific for rheumatoid diseases, (v) antibodies against G‐protein coupled receptors, and (vi) other autoantibodies. The evidence reviewed here clearly highlights that SARS‐CoV‐2 infection may induce humoral autoimmune responses. However, the available studies share number of limitations, such as: (1) the sole presence of autoantibodies does not necessarily implicate the clinically‐relevant risks, (2) functional investigations were rarely performed and it is often unknown whether observed autoantibodies are pathogenic, (3) the control seroprevalence, in healthy, noninfected individuals was often not reported; thus it is sometimes unknown whether the detected autoantibodies are the result of SARS‐CoV‐2 infection or the accidental post‐COVID‐19 detection, (4) the presence of autoantibodies was rarely correlated with symptoms of the post‐COVID‐19 syndrome, (5) the size of the studied groups were often small, (6) the studies focused predominantly on adult populations, (7) age‐ and sex‐related differences in seroprevalence of autoantibodies were rarely explored, (8) genetic predispositions that may be involved in generation of autoantibodies during SARS‐CoV‐2 infections were not investigated, and (9) the autoimmune reactions following infection with SARS‐CoV‐2 variants that vary in the clinical course of infection remain unexplored. Further longitudinal studies are advocated to assess the link between identified autoantibodies and particular clinical outcomes in COVID‐19 convalescents. [ABSTRACT FROM AUTHOR]

Autoimmune diseases develop due to self-tolerance failure in recognizing self and non-self-antigens. Several factors play a role in inducing autoimmunity, including genetic and environmental elements. Several studies demonstrated the causative role of viruses; however, some studies showed the preventive effect of viruses in the development of autoimmunity. Neurological autoimmune diseases are classified based on the targets of autoantibodies, which target intracellular or extracellular antigens rather than neurons. Several theories have been hypothesized to explain the role of viruses in the pathogenesis of neuroinflammation and autoimmune diseases. This study reviewed the current data on the immunopathogenesis of viruses in autoimmunity of the nervous system. [ABSTRACT FROM AUTHOR]

Endometriosis and autoimmune diseases share a hyper-inflammatory state that might negatively impact the embryo–endometrium crosstalk. Inflammatory and immune deregulatory mechanisms have been shown to impair both endometrial receptivity and embryo competence at the implantation site. The aim of this study was to investigate the potential additional impact of co-existing autoimmunity in women affected by endometriosis on the early stages of reproduction. This was a retrospective, multicenter case-control study enrolling N = 600 women with endometriosis who underwent in vitro fertilization–embryo transfer cycles between 2007 and 2021. Cases were women with endometriosis and concomitant autoimmunity matched based on age and body mass index to controls with endometriosis only in a 1:3 ratio. The primary outcome was the cumulative clinical pregnancy rate (cCPR). The study found significantly lower cleavage (p = 0.042) and implantation (p = 0.029) rates among cases. Autoimmunity (p = 0.018), age (p = 0.007), and expected poor response (p = 0.014) were significant negative predictors of cCPR, with an adjusted odds ratio of 0.54 (95% CI, 0.33–0.90) for autoimmunity. These results suggest that the presence of concomitant autoimmunity in endometriosis has a significant additive negative impact on embryo implantation. This effect might be due to several immunological and inflammatory mechanisms that interfere with both endometrial receptivity and embryo development and deserves further consideration. [ABSTRACT FROM AUTHOR]

Abstract Autoantibodies and inflammation are the hallmarks of autoimmune diseases (ADs). Organ‐specific and nonorgan‐specific ADs are divided according to whether the autoimmune reaction is directed against a specific tissue (e.g., thyroid in Hashimoto's thyroiditis) or widely expressed antigens (e.g., cell nuclei in systemic lupus erythematosus [SLE]). SLE is distinguished by the presence of circulating autoantibodies and immune complex deposition, both of which can induce inflammatory damage to many organs. Rheumatoid arthritis (RA), sometimes called inflammatory arthritis, is a systemic AD that affects the joints and causes synovitis. Multiple sclerosis (MS) is a central nervous system inflammatory disease with various neurological and autoimmune symptoms. Links have been reported between RA and SLE as well as between Type 1 diabetes mellitus and MS. Identification of shared genes and biological processes could aid in the discovery of possible treatment targets in these dual ADs. This review article explores the molecular nature and familial inheritance of dual ADs.

The B cell antigen receptor (BCR)-repertoire is capable of recognizing a nearly unlimited number of antigens. Inevitably, the random nature of antibody gene segment rearrangement, needed in order to provide mature B cells, will generate autoreactive specificities. Once tolerance mechanisms fail to block the activation and differentiation of autoreactive B cells, harmful autoantibodies may get secreted establishing autoimmune diseases. Besides the hallmark of autoimmunity, namely IgG autoantibodies, IgM autoantibodies are also found in many autoimmune diseases. In addition to pathogenic functions of secreted IgM the IgM-BCR expressing B cell might be the initial check-point where, in conjunction with innate receptor signals, B cell mediated autoimmunity starts it fateful course. Recently, pentameric IgM autoantibodies have been shown to contribute significantly to the pathogenesis of various autoimmune diseases, such as rheumatoid arthritis (RA), autoimmune hemolytic anemia (AIHA), pemphigus or autoimmune neuropathy. Further, recent studies suggest differences in the recognition of autoantigen by IgG and IgM autoantibodies, or propose a central role of anti-ACE2-IgM autoantibodies in severe COVID-19. However, exact mechanisms still remain to be uncovered in detail. This article focuses on summarizing recent findings regarding the importance of autoreactive IgM in establishing autoimmune diseases. [ABSTRACT FROM AUTHOR]

(1) Background: philosophical views are important to enable a general and multi-systemic view of the potential understanding of autoimmunity in psychiatric disease that is not solely reflected by an immunological viewpoint. (2) Methods: we reviewed current theories of autoimmunity. (3) Results: we propose a novel area view integrating the "self/non-self" and "continuity" model into the expression of varied forms of autoimmunity in psychiatric disease, ranging from protective to harmful autoimmunity consequences framed into micro-systems (nerve cells) and macro-systems (neuronal networks), termed the "multi-systemic dynamic continuum model". (4) Conclusions: autoimmunity's dynamic spectrum is delineated here as something that probably functions as a whole entity to maintain, first of all, human homeostasis in behavior affecting cells or neuronal networks differently, and secondly to prevent psychiatric disease. [ABSTRACT FROM AUTHOR]

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS , SH2B3 , PTPN2 , PTPN22 , CTLA4 , CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, P = 0.002) and the CLEC16A AA genotype (rs12708716, P = 0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (P = 0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (P = 0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups. [ABSTRACT FROM AUTHOR]

This review on the 100th anniversary of the American Thyroid Association summarizes the remarkable progress attained during the past century regarding the pathogenesis and treatment of thyroid autoimmune diseases. Indeed, the general concept of autoimmune diseases in humans was established 70 years ago by thyroid investigators. Graves' disease is a paradigm for the rare occurrence of how autoimmunity can cause disease by stimulating rather than destroying an organ system. Therapeutic advances in the mid 20th century involving administration of thyroid hormones, thionamide drugs, and radioiodine have been hugely beneficial for human health. However, these approaches can only treat, but not cure, thyroid autoimmunity. Investigation of these diseases is facilitated by the identification of a limited number of specific autoantigens, whose molecular cloning has provided much information on their structure. This knowledge has led to highly sensitive and specific diagnostic tests, provided insight into novel aspects regarding the pathogenesis of thyroid autoimmunity, and has opened avenues for the development of new therapeutic agents. Immunotherapy for a cure as opposed to therapy of Graves' disease and Hashimoto's thyroiditis remains the holy grail for the 21st century. [ABSTRACT FROM AUTHOR]